Diabetes mellitus is a disease of the metabolic dysregulation, most notably dysregulation of glucose metabolism, accompanied by long-term vascular and neurologic complications. This metabolic disorder consists of five classes of diabetes: Type 1 diabetes mellitus, also known as insulin-dependent diabetes mellitus or IDDM; Type 2 diabetes mellitus, also know as non-insulin-dependent diabetes mellitus or NIDDM; secondary diabetes, due to other conditions including pancreatitis, endocrine diseases, or ingestion of certain medications; impaired glucose tolerance; and gestational diabetes mellitus (see, e.g., Report of the Expert Committee on the diagnosis and classification of Diabetes mellitus, (1997) Diabetes Care 20:1183).
NIDDM has a prevalence of approximately 6.6% of the US population. The clinical characteristics include onset after 40 years of age, correlation with obesity, and insulin resistance often present with inadequate insulin production. IDDM is occurs with much less frequency than NIDDM. The clinical characteristics of IDDM include juvenile onset, prone to ketosis, absolute insulin deficiency where exogenous insulin is necessary for survival, and the presence of anti-islet cell antibodies.
IDDM is known to have a prolonged asymptomatic of preclinical period (see, e.g., Ziegler, et al. (1990) Diabetes Care 13:762). During this preclinical period, insulin-producing beta cells of the pancreas are progressively destroyed. A normal pancreas contains 1.0-1.5 million islet cells, with 80% of these responsible for insulin secretion. In a clinically presenting IDDM patient, typically 90% of the beta islet cells have been destroyed. Islet Cell Antibodies (ICAs) have been detected as long as 10 years before the clinical appearance of IDDM (see, Ziegler, supra.).
T lymphocyte mediated immune responses are important in the development of most autoimmune diseases, including IDDM, and in transplant and tumor rejection in mammals (see, e.g., Slattery et al., (1990) Nature 345:724-726; Lund et al., (1990) Nature 345:727-729; and Hutchings et al., (1990) J. Autoimmun. 1:101 -109). The destruction of the beta islet cells is believed to be due to an autoimmune response due to T lymphocyte infiltration of the pancreas.
The non-obese diabetic (NOD) mouse is also known to develop IDDM. Spontaneous IDDM occurs with an incidence of 70-90% in female NOD mice at about 18-25 weeks of age. Because this disease exhibits all of the pathological and autoimmune manifestations of the human disease, NOD mice serve as an excellent model for the identification of agents that might prevent IDDM or ameliorate the effects of the disease. IL-10 and antagonists of IL-12 have been shown to lessen the autoimmune component of IDDM in NOD mice (see, U.S. Pat. Nos. 5,827,513 and 6,706,264).
Interleukin-23 (IL-23) is a heterodimeric cytokine comprised of two subunits, i.e., p19 and p40. The p19 subunit is structurally related to IL-6, granulocyte-colony stimulating factor (G-CSF), and the p35 subunit of IL-12. The p40 subunit is also part of the cytokine IL-12, which is composed of p35 and p40. IL-23 mediates signaling by binding to a heterodimeric receptor, comprised of IL-23R and IL-12betal. The IL-12betal subunit is shared by the IL-12 receptor, which is composed of IL-12betal and IL-12beta2. A number of early studies demonstrated that the consequences of a genetic deficiency in p40 (p40 knockout mouse; p40KO mouse) were more severe than those found in a p35KO mouse. Some of these results were eventually explained by the discovery of IL-23, and the finding that the p40KO prevents expression of IL-12, but also of IL-23 (Oppmann, et al. (2000) Immunity 13:715-725; Wiekowski, et al. (2001) J. Immunol. 166:7563-7570; Parham, et al. (2002) J. Immunol 168:5699-708; Frucht (2002) Sci STKE 2002, E1-E3; Elkins, et al. (2002) Infection Immunity 70:1936-1948). IL-23 is known to be necessary for maintaining the chronic inflammation response.
Recently, it has been shown that IL-23 plays a critical role at the end stage of autoimmune mediated disorders such as multiple sclerosis and rheumatoid arthritis (see, Cua, et al. (2003) Nature 421:744-748; and Murphy, et al. (2003) J. Exp. Med. 198:1951-1957.). IL-23 preferentially induces the proliferation of memory T cells, as well as the production of inflammatory mediators, IL-17 and TNFα, from these memory T cells, critical cytokines in inflammatory and autoimmune disorders (see, e.g., Cua, supra; Murphy, supra; and Trinchieri, et al. (2003) Immunity 19:641-644.).
Most current methods to treat the autoimmune inflammatory aspect of IDDM involve the use of broad immunosuppressive agents such as azathioprine, prednisone, and cyclosporin. Such agents, however, can cause damage to liver, kidney, and other organs, and have the undesirable effect of impairing immune protection against infection and other diseases.
There is an unmet need to treat and/or prevent inflammatory and autoimmune disorders, e.g., diabetes in a less toxic manner. The present invention fulfills this need by providing methods of using antagonists of IL-23 or IL-23R.